Advances in Proton Pump Inhibitor Therapy: Elderly Populations

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16 Apr 2010

Older age produces a slight decrease in the elimination rate of omeprazole canadian and increases its bioavailability. Compared with a bioavailability of 58% in younger subjects, the bioavailability of a single 40-mg dose of IR-OME in healthy older subjects was 76%. The extent of metabolite excretion in the urine (70%) was similar to that observed in younger subjects. The plasma half-life was also similar at approximately one hour. Hepatic Impairment In patients with chronic hepatic disease, the bioavailability of IR-OME increases, reflecting a decrease in first-pass metabolism. The plasma half-life increases to approximately three hours, and plasma clearance decreases to about 70 ml/minute.

Figure 2 A, B, Twenty-four-hour gastric

Figure 2 A, B, Twenty-four-hour gastric pH profiles of immediate-release omeprazole (IR-OME). Repeated administration of IR-OME in the morning produces a gastric acidity profile similar to other proton pump inhibitors (PPIs). C, Adding a second bedtime dose of IR-OME abruptly raises the gastric pH and sustains this level throughout the nighttime interval. HS = at bedtime. (From Goldlust B, Hepburn B, Hardiman Y. Am J Gastroenterol 2004;99:S39.)

Renal Impairment

In patients with chronic renal impairment (the creatinine clearance is between 10 and 62 ml/minute per 1.73 m2), the bioavailability of omeprazole tablet is slightly increased and urinary elimination is decreased. The reduced elimination is related to the decrement in creatinine clearance.

PHARMACODYNAMICS

A gastric pH of greater than 4 has long been established as the target for effective mucosal healing. Studies in healthy subjects have found that once-daily dosing of 40 mg and 20 mg of IR-OME maintains the gastric pH above 4 for 77% and 51%, respectively, of a 24-hour period. In these two studies, IR-OME maintained a median gastric pH of 5.2 with the 40-mg dose and 4.2 with the 20-mg dose. The median 24-hour gastric pH exceeded 4 for 18.6 hours with 40 mg and 12.2 hours with 20 mg. The decrease from baseline for integrated gastric acidity (or total accumulated gastric acid) with IR-OME 40 mg was 84%; with 20 mg, the decrease was 82%.

Table 3 Pharmacodynamic Parameters of Proton Pump Inhibitors by Product Labeling

IR-OME Generic Esomeprazole

Canadian Rabeprazole

Pantoprazole

(Zegerid) (canadian Nexium)

(Aciphex generic)

40 mg     20 mg 40 mg

20 mg

30 mg 15 mg

20 mg

40 mg

20 mg

Time gastric 18.6         12.2

16.8

12.7

15.8 11.7

14.4

NA

NA

pH > 4 (hours)
Percentage of time 77%        51%

70%

53%

66% 49%

60%

NA

NA

with gastric pH > 4
Median gastric pH 5.2          4.2

4.9*

4.1*

4.9* 4.0*

3.5

3.8

2.9

IR-OME = immediate-release omeprazole; NA = not available.
* Mean.
Data from package inserts.35, 44-47

Although no head-to-head studies have compared IR-OME with delayed-release, lansoprazole canadian, the duration of time that IR-OME 40 mg and 20 mg maintain the gastric pH above 4 is slightly longer than the values reported in the product labeling for these delayed-release compounds (Table 3). In all cases, given the relatively short plasma half-lives of these medications (about one hour), the extended durations of antisecretory effects probably reflect the irreversible binding to the parietal cell H+/K+ ATPase enzyme by the PPIs.

CLINICAL TRIALS Efficacy

Nocturnal Acid Control

One trial has confirmed the effectiveness of a bedtime dose of IR-OME in controlling nocturnal gastric acidity. Goldlust and colleagues presented data from an open-label study. IR-OME 20 mg was administered once a day one hour before breakfast for seven days to 17 healthy subjects. On the eighth day, the participants received IR-OME 20 mg twice daily, one hour before breakfast and at bedtime (10 p.m., or 2200 hours). Twenty-four-hour gastric pH monitoring was performed on days seven and eight. Figure 3 Median percentage of time that gastric

Figure 3 Median percentage of time that gastric pH stayed above 4 during the nighttime interval (from 10 p.m. to 6 a.m.) following repeated dosing with immediate-release omeprazole (IR-OME) and pantoprazole. For this eight-hour interval, the median time that gastric pH stayed above 4 was significantly greater with IR-OME once daily (q.d.) or twice daily (b.i.d.), compared with pantoprazole once daily (P < .001 for each comparison). (Data from Castell D, et al. Aliment Pharmacol Ther 2005;21: 1467-1474.)

Figure 2 depicts the 24-hour median gastric pH profiles of patients taking IR-OME at the steady state with 40 mg once daily in the morning, 20 mg once daily in the morning, and 20 mg twice daily, in the morning and at bedtime. As shown in Figure 2C, the bedtime dose of IR-OME rapidly raised the gastric pH and sustained this effect for approximately eight hours. The median percentage of nighttime hours during which the gastric pH was above 4 was 87% with twice-daily dosing of 20 mg and 39% with once-daily morning dosing of 20 mg of IR-OME P < .001). Twice-daily administration of 20 mg of IR-OME also significantly reduced the percentage of patients with NAB, compared with 20 mg administered once daily in the morning, namely, 29% (five of 17 patients) versus 76% (13 of 17 patients) (P = .005). Castell and colleagues compared the nighttime gastric pH control of IR-OME suspension with that of delayed-release pantoprazole tablets. (Pantoprazole is currently the only PPI that is FDA-approved to treat nighttime symptoms of GERD.) In the first period of the open-label, two-period crossover trial, patients with a history of nocturnal GERD symptoms were randomly assigned to receive either IR-OME or pantoprazole. IR-OME 40 mg (n = 32) was taken at bedtime (10 p.m.) for six days. On day seven, 15 patients were randomly selected to receive IR-OME 20 mg twice daily, one hour before breakfast and at bedtime; 17 patients received IR-OME 40 mg twice daily, also one hour before breakfast and at bedtime.

Figure 4 Percentage of patients with nocturnal

Figure 4 Percentage of patients with nocturnal acid breakthrough (NAB) during treat­ment with immediate-release (IR-OME) and pantoprazole. IR-OME once daily (q.d.) and twice daily (b.i.d.) produced significantly smaller percentages of patients with NAB (P < .005), compared with pantoprazole once or twice daily. (Data from Castell D, et al. Aliment Pharmacol Ther 2005;21:1467-1474.)

Was administered at 10 p.m. on day one and before dinner on days two through six. On day seven, this dose was given twice: one hour before breakfast and at bedtime). After a 10- to 14-day washout period, patients “crossed over” to the alternate treatment in the second period. As illustrated in Figure 3, statistically significant differences (P < .001) were observed between the once-daily and twice-daily IR-OME suspensions and the comparative pantoprazole regimen in the median percentages of time that the gastric pH was maintained above 4 during the eight-hour nighttime interval (from 10 p.m. to 6 a.m.). For each paired comparison, the median values were as shown in Figure 3. The median nighttime gastric pH values were 4.7 with IR-OME 40 mg and 2 with pantoprazole 40 mg on day six (P < .001). The percentage of patients who experienced NAB was also significantly smaller during IR-OME therapy than with pantoprazole on days six and seven (P < .005 for each comparison) (Figure 4). On day six, significantly fewer patients treated with IR-OME 40 mg (53.1%) experienced NAB than when they had used pantoprazole 40 mg (78.1%%) (P = .005). Twice-daily IR-OME produced a significantly higher median percentage of time during which the gastric pH was maintained above 4, compared with twice-daily pantoprazole during the 24-hour interval (10 p.m. to 10 p.m.). A median gastric pH level greater than 4 was maintained for 87.8% of the 24-hour interval with twice-daily IR-OME 40 mg, compared with 56.9% (P < .001) observed during twice-daily therapy with panto-prazole 40 mg. Figure 5 Median percentage of time

Figure 5 Median percentage of time that the gastric pH stayed above 4 during the 24-hour interval following repeated dosing with immediate-release omepra-zole (IR-OME) and pantoprazole. A median gastric pH above 4 was main­tained for 61.1% of the 24-hour interval for once-daily (q.d.) IR-OME 40 mg, compared with 56.2% for pantoprazole 40 mg twice daily (b.i.d). (Data from Castell D, et al. Aliment Pharmacol Ther 2005;21:1467-1474.)

At steady state, the median percentage of time with the gastric pH above 4 during the 24-hour interval was similar for paired patients taking once-daily IR-OME 40 mg and twice-daily pantoprazole 40 mg (Figure 5). upper GI bleeding in critically ill patients in a multicenter, randomized, double-blind, double-dummy, parallel-group study of 359 patients. These patients, who were undergoing mechanical ventilation in the intensive care unit (ICU) and had Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of 11 or higher and one additional risk factor for upper GI bleeding, were enrolled at 47 sites in the U.S. The patients were assigned to receive either IR-OME suspension via naso-gastric or orogastric tube at a dose of 40 mg twice daily on day one (six to eight hours apart) and 40 mg once daily thereafter (and continuous intravenous [IV] placebo) or IV cimetidine (Tagamet, GlaxoSmithKline), given as a 300-mg bolus. This dose was followed by an infusion of 50 mg/hour thereafter (and placebo oral suspension). Each regimen was administered for up to 14 days. Gastric aspirates were sampled for upper GI bleeding every two hours on the first and second days, then every six hours for the remaining study days. Gastric aspirates were also used to measure pH every two hours on the first and second days and immediately before and one hour after administration of the IR-OME suspension on days 3 to 14. The dose of IR-OME or cimetidine was doubled for patients with two successive gastric aspirates of a pH of 4 or less. A second daily dose of IR-OME 40 mg was administered to patients only on the day when they had two successive gastric aspirates of a pH of 4 or less, whereas the dose of cimetidine was doubled to 100 mg/hour for the duration of the study. Patients were permitted enteral feedings after the third day. Feedings were held for three hours before and for one hour after administration of the IR-OME suspension. The primary efficacy endpoint of this non-inferiority study was the occurrence of clinically significant upper GI bleeding. This was defined as bright-red blood via a nasogastric or an orogastric tube that had not cleared after 5 to 10 minutes of lavage or as persistent Gastroccult-positive coffee-ground material for at least eight consecutive hours on days one and two or for two to four hours on days.
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